Abstract

Background Valproic acid (VPA) is widely prescribed by paediatric neurologists as an antiepileptic drug. VPA-induced hyperammonaemia
can lead to encephalopathy and coma; it is well documented among the paediatric population. Severe urea cycle enzyme deficiencies
are often revealed in early youth when VPA is administered. Such mild genetic deficiencies can remain unnoticed until adulthood
and be discovered if VPA is taken for bipolar disorder.

Purpose To evaluate the frequency of VPA-induced hyperammonaemia in adult psychiatric settings and to sensitise the medical community
to a potentially severe adverse effect of a widely-prescribed drug.

Materials and Methods The study was carried out a two-week period in a psychiatric hospital. It included every full-time hospitalised patient
treated with VPA for at least 4 days (corresponding to 5 drug half-lives). Ammonia and VPA blood measurements were performed
once and an electroencephalogram when ammonia exceeded 70 µM (normal range: 10 to 35 µM). Ethics committee approval was obtained
before starting the study.

Results 122 patients were included in this study. 68 patients (55.8%) presented ammonia blood levels exceeding 35 µM and 4 of them
(3.3%) exceeded 70 µM. One patient reached 118 µM one week after VPA initiation. No encephalographic abnormalities were observed.
No correlation was found between ammonia and total VPA levels. Different oral forms of VPA were used and this study showed
that they affected VPA blood levels.

Conclusions VPA-induced hyperammonaemia is a frequent, generally well-tolerated, adverse effect. Ammonia blood level monitoring combined
with clinical monitoring are essential to avoid hyperammaonemic encephalopathy. Communication within the hospital led to the
medical community becoming aware of the problem and new monitoring recommendations were defined including initial ammonia
level measurement after VPA initiation and biannual monitoring of this biological parameter. Total VPA level determination
doesn’t seem to be useful for predicting hyperammonaemia whereas the importance of measuring the free VPA has recently been
highlighted.